Ovarian and adrenal steroid production: regulatory role of LH/HCG

BACKGROUND: The contribution of the adrenal glands to the total circulating steroid pool in women is not well known. There is evidence that human adrenals express the LH receptor gene and that LH may affect adrenal androgen secretion. METHODS: HCG stimulation tests (a single dose of 5000 IU i.m.) were performed in women at reproductive age (group 1, n = 6, age 21--39 years) before and after treatment with a GnRH agonist for 3 weeks, and in oophorectomized post-menopausal women (group 2, n = 6, 47--59 years) during and after estrogen replacement therapy (ERT). RESULTS: HCG did not stimulate the secretion of cortisol, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS) in group 2. In contrast, in group 1, the basal concentrations of serum 17-hydroxyprogesterone (17-OHP), androstenedione, testosterone and estradiol (E(2)) were stimulated significantly (17-OHP 105%, androstenedione 31%, testosterone 20%, E(2) 136%) by HCG, and the treatment with GnRH agonist decreased the responses. The basal serum concentrations of these steroids were significantly lower in oophorectomized women (17-OHP 57%, androstenedione 46%, testosterone 25%), and HCG did not increase these levels. It can be approximated that the ovarian contribution to the circulating levels of 17-OHP, androstenedione and testosterone is 25--30%, and that the adrenals are the primary source of cortisol, DHEA and DHEAS. CONCLUSION: LH/HCG does not have a major role in the regulation of adrenal steroid synthesis in endocrinologically healthy women.     

The significance of anti-Müllerian hormone concentration in seminal plasma for spermatogenesis

BACKGROUND: The function of anti-Müllerian hormone (AMH) in seminal plasma in adulthood is uncertain. We examined the significance of seminal AMH for spermatogenesis. METHODS: We measured seminal concentrations of AMH in 39 oligozoospermic men (mean age +/- SD, 32.7 +/- 4.3 years) and 10 normal volunteers to examine the association of seminal AMH with spermatogenesis. The seminal concentrations of AMH in oligozoospermic men (149.3 +/- 254.0 pmol/l) were significantly lower than in normal men (249.0 +/- 167.7 pmol/l; P +/- 0.0337). Seminal AMH concentration correlated significantly with sperm concentration (r = 0.339, P = 0.0350) and mean testicular volume (r = 0.440, P = 0.246). The serum concentration of LH (r = - 0.365, P = 0.0241), but not FSH, testosterone or estradiol, correlated significantly with AMH concentration in seminal plasma. CONCLUSIONS: AMH in seminal plasma may be important for sperm production, and is a good marker for Sertoli cell development.     

Inhibitory effect of plasma obtained from hypophysectomized and control women on the assay of bioactive luteinizing hormone

The purpose of this study was to determine the effect of components of female plasma on the value of bioactive luteinizing hormone (LH), especially in the presence of low immunological LH value. Using both an immunoradiometric assay (IRMA) and rat Leydig cell bioassay, immunoreactive (I) and bioactive (B) LH were assessed in plasma collected from women during a gonadotrophin releasing hormone (GnRH) test performed on day 7 of a spontaneous cycle. Two modes of response to an acute administration of GnRH were defined: normal production of gonadotrophins (group I) and excessive secretion (group II) associated with a significant difference in the B/I-LH ratio between the two groups. The B/I-LH ratio did not vary with sampling time during the test in either group. The addition of LH-free plasma collected from hypophysectomized women caused a 30% decrease in testosterone production compared to control values (in the presence or absence of hLH standard). A partial restoration of testosterone production was observed if plasma was first treated with PEG 12%. The inhibitory factor(s) was also present in plasma from ovulatory women, even after treatment by an antibody against the entire LH molecule. The effect of normal (A) or low I-LH plasma (B) on testosterone production varied strongly according to the plasma volume added to the bioassay, as well as to plasma treatments. Diethylether treatment caused a 50% decrease in testosterone secretion for plasma B (but not for A) whereas a diminution of the steroidogenesis is observed after a PEG treatment of plasma A (but not for B), suggesting that different inhibitory factors are present in plasmas A and B. Therefore the LH bioactivity measured in the rat Leydig cell assay, in terms of testosterone output, seems to represent a balance between the LH molecule and the presence of inhibitory factors in the plasma.     

Insulin-like factor 3 levels in amniotic fluid of human male fetuses

BACKGROUND: Rodent studies suggest that the peptide hormone insulin-like factor 3 (Insl3) made by the fetal testis is responsible for the first transabdominal phase of testicular descent, and may be affected by xenobiotics to disrupt male reproductive tract development. To date, there is very little information on the production of INSL3 by the human fetus during gestation. The objective of the present study was to determine the concentrations and time course during pregnancy of INSL3 and testosterone production in human fetuses and their associations with maternal characteristics, pregnancy complications and outcome. METHODS: This is a retrospective cohort study in which women who contributed amniotic fluid specimens to a bank from 2003-2006 were followed to determine their pregnancy complications and pregnancy outcome. Amniotic fluid specimens were collected from the Reproductive Genetics Laboratory of the Hospital of the University of Pennsylvania subsequent to routine amniocentesis. INSL3 and total testosterone levels were measured in amniotic fluid (from n = 50 female, n = 237 male fetuses) by validated immunoassays and correlated with maternal characteristics, pregnancy complications and outcomes. RESULTS: INSL3 was only detectable in amniotic fluid from male fetuses, and highest levels occurred from weeks 15-17 of gestation. INSL3 concentration was positively associated with increased birth weight, the occurrence of pre-eclampsia and advanced maternal age, but not with testosterone levels. CONCLUSIONS: INSL3 concentration in human amniotic fluid is potentially predictive of fetal sex and pre-eclampsia, and presumably reflects the functioning of the fetal Leydig cell population.     

The Role of Foxo3 in Leydig Cells

Purpose

Foxo3 in female reproduction has been reported to regulate proliferation of granulose cells that form follicles. There are no reports so far that discuss on the role of Foxo3 in males. This study was designed to outline the role of Foxo3 in the testes.

Materials and Methods

Testes from mice at birth to postpartum week (PPW) 5 were isolated and examined for the expression of Foxo3 using immunostaining. To elucidate role of Foxo3 in Leydig cells, R2C cells were treated with luteinizing hormone (LH) and the phosphorylation of Foxo3. Testosterone and steroidogenic acute regulatory (StAR) protein levels were measured after constitutive active [triple mutant (TM)] human FOXO3 adenovirus was transduced and StAR promoter assay was performed.

Results

Foxo3 expression in the testicles started from birth and lasted until PPW 3. After PPW 3, most Foxo3 expression occurred in the nuclei of Leydig cells; however, at PPW 5, Foxo3 was expressed in both the nucleus and cytoplasm. When R2C cells were treated with luteinizing hormone, Foxo3 phosphorylation levels by AKT increased. After blocking the PI3K pathway, LH-induced phosphorylated Foxo3 levels decreased, indicating that LH signaling regulates Foxo3 localization. When active FOXO3-TM adenovirus was introduced into a Leydig tumor cell line, the concentrations of testosterone and StAR protein decreased. When FOXO3 and a StAR promoter vector were co-transfected into HEK293 cells for a reporter assay, FOXO3 inhibited the StAR promoter.

Conclusion

FOXO3 affects testosterone synthesis by inhibiting the formation of StAR protein. LH hormone, meanwhile, influences Foxo3 localization, mediating its function.     

In-vivo ovarian androgen responses to recombinant FSH with and without recombinant LH in polycystic ovarian syndrome

BACKGROUND: Effects of exogenous LH on ovarian androgen secretion during ovulation induction have not been clearly characterized in polycystic ovarian syndrome (PCOS). The purpose of this study was to compare androgen secretion in PCOS women during ovarian stimulation with either recombinant FSH (rFSH) alone or combined with recombinant LH (rLH). METHODS: Clomiphene-resistant women with PCOS were allocated, in a factorial study design, to receive either daily injections of rFSH (n = 24) or rFSH + rLH (n = 24) in a 1:1 ratio starting: (i) on day 2-3 of progestogen-induced menses (n = 8); (ii) after 6 weeks of GnRH agonist treatment (nafarelin, 400 micro g twice daily; n = 8); or (iii) after nafarelin treatment as in (ii) plus dexamethasone (n = 8). The effects of rFSH with rFSH + rLH under these three hormone conditions on serum LH, 17alpha-hydroxyprogesterone (17-OHP), androstenedione (DeltaDelta(4)) and testosterone were contrasted by analysis of variance with specific treatment days as a repeated measures factor. RESULTS: Pre-study hormone levels were similar for all groupings. Nafarelin significantly suppressed LH levels, which remained at the lower limit of assay sensitivity (0.5 IU/l) during stimulation with rFSH but increased significantly to >1 but <2 IU/l when rLH was added. As expected, 17-OHP, DeltaDelta(4) and testosterone levels fell following nafarelin treatment. Dexamethasone further suppressed 17-OHP, DeltaDelta(4) and testosterone levels and unmasked a small but significant rise in these ovarian steroids 24 h following the first dose of rFSH + rLH, a rise that was absent with rFSH alone. Secretion of these steroids then appeared to 'catch-up' after 5 days of rFSH stimulation. CONCLUSIONS: Despite profound LH, 17-OHP, DeltaDelta(4) and testosterone suppression, comparable E(2) response, follicle development and successful pregnancies in PCOS subjects receiving rFSH alone to those receiving rFSH + rLH would argue that circulating LH at levels as low as 0.5 IU/l are sufficient to sustain adequate follicle development and function when FSH is present in abundance. Whether the observed dichotomy between rFSH and rFSH + rLH treatment in temporal secretion patterns reflects a greater reliance on evolving paracrine mechanisms as the follicles mature under profound LH suppression remains to be explored but may influence the optimal LH threshold for ovulation induction in PCOS.     

Morphometric analysis of peri-implantation endometrium in patients having excessively high oestradiol concentrations after ovarian stimulation

The present study investigated whether high oestradiol concentrations after ovarian stimulation in infertile women affect endometrial development around the time of implantation. The glandular and stromal components of the endometrium were assessed by morphometric criteria. Endometrial biopsies were taken on day 7 (+/-1) after the ovulating dose of human chorionic gonadotrophin in stimulation cycles and on day 7 after the LH surge in natural cycles. Women (n = 38) undergoing assisted reproduction treatment were evaluated: 12 women in natural cycles, 11 women in stimulation cycles with oestradiol <20,000 pmol/l and failed fertilization after oocyte collection (moderate responders) and 15 women with an oestradiol concentration of > or =20,000 pmol/l in stimulation cycles (high responders). High responders showed delayed glandular maturation and advanced stromal morphology, whereas moderate responders demonstrated synchronous development of glandular and stromal features. In natural cycles, the glands were in phase. The effect of excessively high oestradiol concentrations could be explained by quantitative evaluation of the endometrial biopsies as gland--stromal dyssynchrony, which indicates a deficient secretory transformation of the endometrium that represents a suboptimal endometrial environment for implantation. This substantiates our previous clinical observation of significantly lower pregnancy rates in IVF cycles of women with high oestradiol concentrations (> or =20,000 pmol/l).     

Comparison of components of the testis interstitium with testosterone secretion in hamster,rat, and guinea pig testes perfused in vitro

Components of the testis and cytoplasmic organelles in Leydig cells were quantified with morphometric techniques in hamster, rat, and guinea pig. Testosterone secretory capacity per gram of testis and per Leydig cell in response to luteinizing hormone (LH) (100 ng/ml) stimulation was determined in these three species from testes perfused in vitro. Numerous correlations were measured among structures, and between structures and testosterone secretion, to provide structural evidence of intratesticular control of Leydig cell function. Testosterone secretion per gm testis and per Leydig cell was significantly different in the three species: highest in the guinea pig, intermediate in the rat, and lowest in the hamster. The volume of seminiferous tubules per gm testis was negatively correlated, and the volumes of interstitium. Leydig cell, and lymphatic space per gm testis were positively correlated with testosterone secretion. No correlations were observed between volumes of blood vessels, elongated spindle-shaped cells, or macrophages per gm testes and testosterone secretion. The average volume of a Leydig cell and the volume and surface area of smooth endoplasmic reticulum (SER) and peroxisomes per Leydig cell were positively correlated, and the volume of lysosomes and surface area of inner mitochondrial membrane per Leydig cell were negatively correlated with testosterone secretion. No correlations were observed between volume and surface area of rough endoplasmic reticulum (RER), Golgi apparatus, and lipid, and volume of ribosomes, cytoplasmic matrix, and the nucleus with testosterone secretion per Leydig cell. These results suggest that Leydig cell size is more important than number of Leydig cells in explaining the difference in testosterone-secreting capacity among the three species, and that this increase in average volume of Leydig cell is associated specifically with increased volume and surface are of SER and peroxisomes. An important unresolved question is what is the role of peroxisomes in Leydig cell steroidogenesis.     

Changes in luteinizing hormone and insulin secretion in polycystic ovarian syndrome

Uncertainties regarding the pathogenetic changes underlying the polycystic ovarian syndrome (PCOS) have been reported. The aim of this study was to investigate the endocrine and metabolic features of PCOS patients in relation to luteinizing hormone (LH) secretion. Androgen assays, oral glucose tolerance tests, hyperinsulinaemic euglycaemic clamps and gonadotrophin releasing hormone (GnRH) tests were performed in 100 patients. Sixty-six patients scheduled as hyperinsulinaemic and 34 as normoinsulinaemic showed similar concentrations of LH, follicle stimulating hormone (FSH), LH/FSH ratio, and LH response to GnRH testing. Hyperinsulinaemic subjects showed higher body mass index (BMI), insulin resistance, testosterone and free androgen index levels compared with those of normoinsulinaemic subjects; when clustered in relation to their LH basal concentrations, the two groups obtained differed only in androstenedione concentrations. Considering both insulin and LH plasma concentrations, four groups were obtained. Hyperinsulinaemia and hyper-LH secretion were not related in 54% and coexisted in the same subjects in 26% of cases. Hyperinsulinaemia as well as hyper-LH secretion affected the expression of the syndrome; the insulinaemia was directly correlated with testosterone concentrations and all metabolic parameters that affected the free androgen index. The LH concentrations were related to androgen production and were independent of BMI and insulin concentrations. It is concluded that the degree of hormonal alteration is the final sum of such pathogenetic factors.     

银杏叶提取物对2型糖尿病大鼠睾酮水平、LHR和StAR mRNA表达的影响

目的： 探讨银杏叶提取物(EGB)在2型糖尿病大鼠睾酮合成中的作用及其对黄体生成素受体(LHR)、类固醇激素合成急性调节蛋白(StAR)基因表达的影响。方法: 雄性SD大鼠30只，随机均分成3组：正常对照组、2型糖尿病组、EGB 治疗组。后2组给以高脂饮食加小剂量(30 mg/kg)链脲佐菌素(STZ)诱导2型糖尿病大鼠模型，EGB治疗组予EGB50mg·kg^-1·d^-1灌胃12周，正常对照组及2型糖尿病组灌服等容积生理盐水。测定各组大鼠血葡萄糖、血胰岛素、血LDL-c含量；称各组大鼠睾丸重量，并用光镜和透射电镜观察大鼠睾丸组织的形态学改变； ELISA法检测血清黄体生成素(LH)、睾酮(T)水平；RT－PCR检测睾丸组织中LHR、StAR mRNA表达水平。结果: 与正常组相比，糖尿病组大鼠血清T、LH含量及睾丸组织的StAR mRNA含量明显降低，血糖、血胰岛素、LDL-c及LHR mRNA含量显著升高，睾丸重量明显减轻；光镜下主要表现为睾丸曲细精管内生精细胞数量减少及生精阻滞，透射电镜下主要见到间质细胞(Leydig cell)及支持细胞内线粒体、内质网等细胞器空泡样变及扩张。EGB治疗组睾丸组织病理改变较轻，血清T 、LH含量及睾丸组织StAR mRNA含量明显高于糖尿病组，血糖、血胰岛素、LDL-c及睾丸组织LHR mRNA含量低于糖尿病组。结论: EGB可提高2型糖尿病大鼠T的合成，其机制可能与改善糖脂代谢紊乱，调节LHR、StAR mRNA表达有关。     

Effects of androstenedione, insulin and luteinizing hormone on steroidogenesis in human granulosa luteal cells

BACKGROUND: The present study was conducted to investigate the effect of androstenedione, insulin and LH on human granulosa cell oestrogen and progesterone production. We postulated that elevated concentrations of androstenedione, insulin and LH may be important modulators of granulosa cell steroidogenesis. METHODS: Granulosa cells obtained in connection with IVF procedures were cultured for a total of 4 days in serum-free medium containing androstenedione (10(-6) mol/l). We tested the effect of androstenedione (10(-5) mol/l) on insulin (0-800 microIU/ml), LH (1-10 ng/ml) as well as on insulin + LH-stimulated oestrogen and progesterone production. RESULTS: Insulin increased the basal secretion of steroid hormones, and furthermore augmented LH-stimulated oestrogen and progesterone accumulation in granulosa cell cultures. Androstenedione (10(-5) mol/l) stimulated basal oestrogen production, but significantly reduced (32-58%) insulin + LH-stimulated oestrogen and progesterone secretion (P < 0.05). CONCLUSION: These results suggest that high androstenedione concentrations may act directly to impair insulin augmentation of LH-stimulated oestradiol and progesterone production in cultured human granulosa luteal cells. This is compatible with the hypothesis that high androgen levels may inhibit oestrogen production in polycystic ovary follicles, and as such may contribute to anovulation and infertility in women with polycystic ovary syndrome.     

Androgen-forming stem Leydig cells: identification, function and therapeutic potential

Leydig cells are the primary source of testosterone in the male, and differentiation of Leydig cells in the testes is one of the primary events in the development of the male body and fertility. Stem Leydig cells (SLCs) exist in the testis throughout postnatal life, but a lack of cell surface markers previously hindered attempts to obtain purified SLC fractions. Once isolated, the properties of SLCs provide interesting clues for the ontogeny of these cells within the embryo. Moreover, the clinical potential of SLCs might be used to reverse age-related declines in testosterone levels in aging men, and stimulate reproductive function in hypogonadal males. This review focuses on the source, identification and outlook for therapeutic applications of SLCs. Separate pools of SLCs may give rise to fetal and adult generations of Leydig cell, which may account for their observed functional differences. These differences should in turn be taken into account when assessing the consequences of environmental pollutants such as the phthalate ester, diethylhexylphthalate (DEHP).     

Hypersecretion of luteinizing hormone and ovarian steroids in women with recurrent early miscarriage

Polycystic ovary syndrome is associated with hypersecretionof luteinizing hormone (LH) which has been implicated in theaetiology of early pregnancy loss. Although 82% of women withrecurrent early loss have polycystic ovaries on ultrasound imaging,random serum LH concentrations are normal. In the present study,we have obtained further information from serial samples concerningthe cyclical patterns of gonadotrophin and sex steroid secretionin these women. Twenty-one women with recurrent early pregnancyloss and 10 multiparous controls were investigated; 81% of themand one of ten control subjects had polycystic ovaries. Meanmid-follicular and mid-luteal serum LH and follicle stimulatinghormone (FSH) levels were similar in both groups. Seventeenwomen with pregnancy loss had either raised urinary LH excretionor a premature LH surge; one control subject had a prematureLH surge. Total LH excretion during the cycle and mean follicularphase serum testosterone was significantly greater with earlypregnancy loss than in the control group, the difference inLH being greatest in the early luteal phase. Urinary oestrone-3-glucuronideexcretion was raised in the early luteal phase of the cyclein the group with early pregnancy loss; there was no differencebetween the groups in pregnanediol-3-glucuronide excretion.These data demonstrate abnormalities in LH secretion in 81%of women with recurrent fetal loss. Inappropriately raised LHlevels may have adverse effects on the developing oocyte orendometrium either directly, or indirectly by causing an elevationin testosterone and oestrogen levels.     

Decrease in luteinizing hormone biological activity/immunoreactivity ratio in elderly men

Basal serum concentrations of biologically active luteinizing hormone (BIO-LH), immunoreactive LH (RIA-LH) and testosterone (T), as well as the LH bioactivity/immunoreactivity (B/I) ratios were measured in 57 healthy, elderly male volunteers aged 60–94 yr. As a reference group, 53 healthy young men aged 18–49 yr were also studied. LH biological activity was assessed by an in vitro bioassay method based on testosterone production by mechanically dispersed mouse Leydig cell preparations in response to graded doses of LH. The mean BIO-LH and RIA-LH serum concentrations in the elderly men showed a significant increase (two- and three-fold, respectively, P < 0.001, as compared with the values in the young men, whereas the mean LH B/I ratio and T values were significantly decreased ( − 22% and − 43%, respectively, P < 0.001). The decrease in the LH B/I ratio in elderly men led us to hypothesize that the ageing pituitary may secrete molecules of LH possessing a reduced bioactivity in relation to their immunoreactivity.     

The effect of gonadotrophins with differing LH/FSH ratios on the secretion of the various species of inhibin in women receiving IVF

We have measured secretory patterns of inhibin A, B, total alpha inhibin, pro-alphaC inhibin and oestradiol in women following pituitary suppression who were randomised into two groups to receive either urinary gonadotrophin (25:75 IU/ampoule of luteinizing hormone (LH) and follicle stimulating hormone (FSH; Normegon; n = 11) or recombinant (r)FSH (75 IU/ampoule of FSH alone, n = 16). The women were of similar age (approximately 33 years) and length of infertility (approximately 4 years) and had a normal endocrine evaluation. Plasma FSH, LH, oestradiol, inhibin A, B, pro-alphaC and total alpha inhibin were measured by immunoassay prior to and following gonadotrophin stimulation. Immunoactive FSH, LH and oestradiol blood concentrations following pituitary down regulation were similar in the two groups being <2.0, <3.6 IU/l and <82 pmol/l respectively. The units of FSH given (2230 versus 2764 IU; Normegon versus rFSH), duration of treatment (9.1 versus 9.4 days) and number of follicles of > or =14mm on the day of human chorionic gonadotrophin (HCG) administration (17 versus 14) were also similar. Inhibin A or B concentrations rose similarly during Normegon or rFSH administration, peaking at days 9-11. Total alpha and pro-alphaC inhibin concentrations were lower (P < 0.05) in the rFSH group during days 10 and 11 of treatment being 18.9 +/- 15.9 ng/ml (Normegon) and 4.6 +/- 2.8 ng/ml (rFSH) for total alpha inhibin and 8.5 +/- 6.8 ng/ml (Normegon) and 2.8 +/- 1.6 ng/ml (rFSH) for pro-alphaC inhibin on day 10. Overall, higher total alpha inhibin concentrations were associated with more mature follicles and oocytes, greater fertilization rates and better quality embryos. We conclude that inhibin A and B secretion was similar in both groups and is primarily controlled by FSH, whereas total alpha inhibin and pro-alphaC increased preferentially in the Normegon group over the rFSH group, indicating that they are, in part, stimulated by LH.     

Comparison of LH concentrations in the early and mid-luteal phase in IVF cycles after treatment with HMG alone or in association with the GnRH antagonist Cetrorelix

Luteinizing hormone (LH) is mandatory for the maintenance of the corpus luteum. Ovarian stimulation for IVF has been associated with a defective luteal phase. The luteal phases of two groups of patients with normal menstrual cycles and no endocrinological cause of infertility were retrospectively analysed in IVF cycles. Thirty-one infertile patients stimulated with human menopausal gonadotrophins (HMG) for IVF to whom the gonadotrophin-releasing hormone (GnRH) antagonist Cetrorelix 0.25 mg was also administered to prevent the LH surge (group I) were compared with 31 infertile patients stimulated with HMG alone (group II). Despite differences in the stimulation outcome, luteal LH serum concentrations were similar in the two groups. LH values dropped from 2.3 +/- 1 IU/l on the day of human chorionic gonadotrophin (HCG) administration to 1.1 +/- 0.7 IU/l on day HCG +2 in group I (P < 0.0001) and from 5.1 +/- 3 to 1.2 +/- 1.7 IU/l (P < 0.0001) in group II. In the mid-luteal phase, LH concentrations were low in both groups. Our results suggest that suppressed LH concentrations in the early and mid-luteal phase may not be attributed solely to the GnRH-antagonist administration. Pituitary LH secretion may be inhibited by supraphysiological steroid serum concentrations via long-loop feedback and/or by the central action of the exogenously administered HCG via a short-loop mechanism.     

Expected contribution to serum oestradiol from individual ovarian follicles in unstimulated cycles

Data relating serum oestradiol concentration to follicle size in unstimulated cycles are lacking. We provide precise data on serum concentrations expected for any follicle diameter (FD) in the mid- to late follicular phase. Infertile women (n = 35) with apparently normal ovulatory cycles were studied in detail in 128 unstimulated monofollicular cycles leading to IVF. Using mathematical modelling to account for repeated cycles in the same woman, the relationship between serum oestradiol and FD was explored and reference ranges for serum oestradiol at individual FD were calculated. Serum oestradiol concentrations [number of patients, geometric mean, 95% confidence interval (CI)] at the onset of the LH surge were higher in 'fertilized' cycles (73, 1279, 1180-1378 pmol/l) compared with 'unfertilized' cycles (31, 1055, 929-1197 pmol/l, P: = 0.008) and 'no oocyte' cycles (24, 1064, 922-1227 pmol/l, P: = 0.03) respectively. In 'fertilized' cycles, oestradiol concentrations rose exponentially with FD and for each size of follicle the oestradiol distribution was skewed. Functional oocyte competence varied in apparently normal ovulatory cycles and was correlated with pre-ovulatory serum oestradiol but not FD. Serum oestradiol varies within wide limits for maturing follicles of any given diameter prior to the onset of the LH surge.     

Infant feeding with soy formula milk: effects on puberty progression, reproductive function and testicular cell numbers in marmoset monkeys in adulthood

BACKGROUND: This marmoset study addresses concerns about feeding human male infants with soy formula milk (SFM). METHODS: From age 4 to 5 days, seven male co-twin sets were fed standard formula milk (SMA) or SFM for 5-6 weeks; blood samples were subsequently collected at 10-week intervals. Testes from co-twins killed at 120-138 weeks were fixed for cell counts. RESULTS: SFM- and SMA-fed twins showed normal weight gain; puberty started and progressed normally, based on blood testosterone measurements. Body weight, organ weights (prostate, seminal vesicles, pituitary, thymus and spleen) and penis length were comparable in co-twins. All SMA- and 6/7 SFM-fed males were fertile. Unexpectedly, testis weight (P = 0.041), Sertoli (P = 0.025) and Leydig cell (P = 0.026) numbers per testis were consistently increased in SFM-fed co-twins; the increase in Leydig cell numbers was most marked in males with consistently low-normal testosterone levels. Seminiferous epithelium volume per tubule showed a less consistent, non-significant increase in SFM-fed males; raised germ cell numbers per testis, probably due to increased Sertoli cells, conceivably resulted in larger testes. Average lumen size, although greater in SFM-fed group, was inconsistent between co-twins and the difference was not significant. CONCLUSIONS: Infant feeding with SFM has no gross adverse reproductive effects in male marmosets, though it alters testis size and cell composition, and there is consistent, if indirect, evidence for possible 'compensated Leydig cell failure'. Similar and perhaps larger changes likely occur in adult men who were fed SFM as infants.